Cancer Chemother Pharmacol (2012) 69:1443–1448 DOI 10.1007/s00280-012-1849-3
O R I G I N A L A R T I CL E
The T393C polymorphism of GNAS1 as a predictor for chemotherapy sensitivity and survival in advanced non-smallcell lung cancer patients treated with gemcitabine plus platinum Fa-Jun Xie · Peng Zhao · Jun-Yan Kou · Wei Hong · Li Fu · Lin Hu · Dan Hong · Dan Su · Yun Gao · Yi-Ping Zhang
Received: 9 October 2011 / Accepted: 6 February 2012 / Published online: 28 February 2012 © Springer-Verlag 2012
Abstract Purpose The GNAS1 gene is linked to proapoptotic signaling and correlates closely with clinical outcomes in many human cancers. The aim of this study was to evaluate whether the T393C polymorphism of the GNAS1 gene could be used as a chemotherapy sensitivity and prognosis predictive marker of advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum (GP). Methods In this study, we performed the PCR-restriction fragment length polymorphism assay to examine the genotypes of the GNAS1 T393C polymorphism in 131 peripheral blood DNA specimens from advanced NSCLC patients with GP treatment. Results The frequencies of the CC, CT, and TT genotypes in 131 advanced NSCLC cases were 25.2, 47.4, and 26.7%, Fa-Jun Xie and Peng Zhao contribute equally to this work. F.-J. Xie · W. Hong · L. Hu · D. Hong · Y.-P. Zhang (&) Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou City, Zhejiang Province 310022, China e-mail:
[email protected] F.-J. Xie · D. Su · Y. Gao · Y.-P. Zhang Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang, China P. Zhao Department of Medical Oncology, The First AYliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China J.-Y. Kou Department of Medical Oncology, Hangzhou Cancer Hospital, Zhejiang, China L. Fu Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
respectively. The favorable TT genotype was signiWcantly correlated with better overall survival (OS; P < 0.05) and longer progress-free survival (PFS; P < 0.05) compared with the CT or CC genotype. In the multivariate Cox proportional hazards model, the GNAS1 T393C polymorphism was independently associated with overall survival after adjusting the clinicopathological factors (P < 0.05). Conclusions This study suggests that the TT genotype of the GNAS1 T393C polymorphism could be an independent prognostic marker to predict chemotherapy sensitivity, favorable OS and PFS in advanced NSCLC patients with GP treatment. Keywords GNAS1 · Polymorphism · Advanced NSCLC · Chemotherapy · Prognosis
Introduction Lung cancer is the leading cause of cancer-related mortality, of which non-small-cell lung cancer (NSCLC) accounts for approximately 85% [1]. Although surgery can be curative at the early stages of NSCLC, the majority of patients with NSCLC have advanced and metastatic disease, which makes it is not amenable to curative resection at diagnosis. The combination of gemcitabine and platinum (cisplatin or carboplatin) is one of the feasible and eVective Wrst line treatments for patients with advanced disease and has showed improved overall survival [2]. One of the most important mechanisms for anti-cancer drugs is induction of apoptosis in cancer cells. However, patients with similar clinical characteristics are diVerent with response to platinum-based chemotherapy, the variant reactions may be aVected by individual gene polymorphism of patient. The Gs protein subunit (GNAS1) gene has been found to play an important role in promoting tumor cells apoptosis
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[3]. There is increasing evidence that a common synonymous single nucleotide polymorphism (SNP) in exon 5 (T393C) of the GNAS1 gene is associated with the prognosis of human malignancies [3–7]. Frey et al. [8] have showed the genotypes of the GNAS1 T393C polymorphism are associated with altered Gs expression. Down-regulation of Gs could weaken the function of Gs-dependent apoptotic pathway and suppress chemotherapy-induced cancer cell death, resulting in faster cancer progression and shorter patients’ survival which may make the anti-cancer drugs less eVective. Until now, the polymorphism state of the GNAS1 T393C in NSCLC, as well as its association with the chemotherapy sensitivity and prognostic signiWcance, has not yet been investigated. In this study, we Wrst conducted a single-hospital-based respective analysis of 131 patients with advanced NSCLC to elucidate a potential correlation between the T393C genotypes and the clinical outcomes of NSCLC patients after platinumbased doubled chemotherapy. Our results suggest that the TT genotype of the GNAS1 T393C polymorphism was signiWcantly associated with chemotherapy sensitivity and better survival of advanced NSCLC. Thus, the T393C polymorphism could serve as an useful predictive marker in guiding the physician for the selection of an optimal treatment regimen.
Cancer Chemother Pharmacol (2012) 69:1443–1448
Chemotherapy regimens Patients with NSCLC have received one of the following chemotherapy treatments: carboplatin AUC 5 mg/mL min on day 1 plus gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks, or carboplatin was replaced with cisplatin 75 mg/m2 on day 1. Each treatment was repeated for two to six cycles, unless unacceptable toxicity, disease progression or patients’ refusal to continue treatment. DNA extraction and genotyping For the genotyping of T393C polymorphism, peripheral blood genomic DNA from patients was extracted using Qiagen blood mini kit (Qiagen, Germany) according to the manufacturer’s protocol. Genomic DNA was subjected to PCR for 30 cycles of ampliWcation with the following pair of primers: Fw: 5⬘-CTCCTAACTGACATGGTGCAA-3⬘ and Rv: 5⬘- TAA GGCCACACAAGTCGGGGT-3⬘. The 345 bp PCR products were digested using the restriction enzyme FokI and analyzed on a 2% agarose gel. The unrestricted products (345 bp) represent the TT genotype; the completely restricted products (259 and 86 bp) represent the CC genotype. Statistical analysis
Patients and methods Patients and clinical samples We collected peripheral blood samples from patients diagnosed with NSCLC pathologically prior to chemotherapy at the Zhejiang Province Cancer Hospital (Zhejiang, China) between January 2008 and December 2010. Patients were enrolled in this study according following criteria: (1) histologically or cytologically conWrmed NSCLC; (2) stage IIIB or IV disease; (3) age no more than 72; (4) Eastern Cooperative Oncology Group PS of 2 or less; (5) one or more measurable or assessable lesions; (6) life expectancy of more than 4 weeks; and (7) none of the patient had received chemotherapy or radiotherapy previously. Patients were excluded if they had symptomatic brain metastasis, malignancies other than NSCLC within the last 5 years. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), and all responses were evaluated at least 6 weeks after initial assessment, that is, complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) on the basis of change in lesion size derived from CT scans. Written informed consent was obtained from all patients enrolled in this study. The study has been approved by the Ethics and ScientiWc Committees of Zhejiang Province Cancer Hospital.
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Statistical analysis was performed with the SPSS standard version 16.0 (SPSS Inc., Chicago, IL). Survival curves and the univariate analysis were analyzed by the Kaplan–Meier method. The prognostic value of diVerent variables for clinical outcomes was estimated by multivariate analysis using the Cox regression model. The association between the GNAS1 T393C polymorphism and clinicopathological characteristics was assessed by chi-square test. DiVerences were considered signiWcant when P < 0.05.
Results Patient characteristics and eYcacy of treatment A total of 131 patients with advanced NSCLC were recruited into this study, of which 88 were men and 33 were women. The mean age of patients was 54 § 10.4 years (ranging from 25 to 72 years old). All patients were nativeChinese of Asian ethnicity. Staging was based upon the 7th edition of AJCC tumor-node-metastasis (TNM) staging system. There were 55 (42.0%)never smokers and 76 (58%) smokers. Of the 131 patients, 25 (19.1%) had Stage IIIB disease and 106 (80.9%) had stage IV disease. None of the patients had CR, while 40 patients had PR, 66 had SD, and 25 had PD. The median progress-free survival (PFS) was 5.70 months (95% CI, range 5.11–6.29 months), while
Cancer Chemother Pharmacol (2012) 69:1443–1448 Table 1 Association between the GNAS1 T393C genotypes and clinical characteristics of patients with advanced NSCLC (n = 131)
Characteristics
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All
GNAS1 T393C genotype CC
CT
P TT
Age (years)
